Introduction
Retevmo (selpercatinib) is an oral, small molecule kinase inhibitor developed by Eli Lilly and Company. It represents a significant advancement in precision medicine as a highly selective and potent RET (Rearranged during Transfection) kinase inhibitor. Retevmo received accelerated FDA approval in May 2020 for the treatment of specific RET-altered cancers, marking a paradigm shift in the management of these malignancies.
Mechanism of Action
Retevmo works through selective inhibition of RET receptor tyrosine kinase, which includes wild-type RET and various mutated RET isoforms. RET alterations (fusions or mutations) lead to constitutive activation of RET signaling, promoting uncontrolled cell growth and survival. Selpercatinib binds to the ATP-binding pocket of RET kinase, inhibiting autophosphorylation and subsequent downstream signaling pathways. The drug demonstrates high specificity for RET with minimal activity against other kinases, resulting in a favorable therapeutic index.
Indications
Retevmo is approved for:
- Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC)
- Adult and pediatric patients (≥12 years) with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy
- Adult and pediatric patients (≥12 years) with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
Dosage and Administration
Standard dosing:- 160 mg orally twice daily (approximately every 12 hours) with or without food
- For severe (Grade 3-4) adverse reactions: interrupt therapy until resolution or improvement, then resume at reduced dose (120 mg twice daily)
- If severe adverse reactions recur: further reduce to 80 mg twice daily
- If intolerable at 80 mg twice daily: permanently discontinue
- Hepatic impairment: No dose adjustment recommended for mild to moderate impairment; not studied in severe impairment
- Renal impairment: No dose adjustment recommended for mild to moderate impairment; not studied in severe impairment
- Pediatric patients: Safety and effectiveness established in patients ≥12 years with body surface area ≥1.5 m²
Pharmacokinetics
Absorption: Median Tmax is 2 hours; administration with high-fat meal decreases AUC by 13-17% and Cmax by 33-45% Distribution: Mean volume of distribution is 321 L; protein binding is 96% Metabolism: Primarily metabolized by CYP3A4 and UGT1A1 Elimination: Mean elimination half-life is 32 hours; 69% excreted in feces (14% unchanged) and 24% in urine (6.5% unchanged)Contraindications
- Hypersensitivity to selpercatinib or any component of the formulation
- No other absolute contraindications identified
Warnings and Precautions
Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.6% of patients. Monitor ALT/AST prior to initiation, every 2 weeks during first 3 months, then monthly thereafter. QT interval prolongation: Dose-dependent QTc prolongation observed. Monitor ECG and electrolytes in patients with congenital long QT syndrome, congestive heart failure, or electrolyte abnormalities. Hypertension: Hypertension reported in 35% of patients. Monitor blood pressure regularly and initiate or adjust antihypertensive therapy. Hemorrhagic events: Serious hemorrhagic events occurred in 2.3% of patients. Monitor for signs and symptoms of bleeding. Hypersensitivity reactions: Grade 3 hypersensitivity reported in 1.3% of patients. Risk of impaired wound healing: Withhold Retevmo for at least 7 days prior to elective surgery and for at least 2 weeks after major surgery.Drug Interactions
Strong CYP3A inhibitors: Avoid concomitant use (e.g., ketoconazole, itraconazole, clarithromycin) Strong CYP3A inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) Acid-reducing agents: Separate administration by at least 2 hours QT-prolonging drugs: Avoid concomitant use with other drugs known to prolong QT intervalAdverse Effects
Most common (≥25%): Increased AST (51%), increased ALT (45%), hyperglycemia (44%), leukopenia (42%), diarrhea (38%), hypocalcemia (36%), fatigue (35%), hypertension (35%), nausea (34%), constipation (34%), increased creatinine (33%), abdominal pain (32%) Serious adverse reactions: Hepatotoxicity (2.6%), QT prolongation (4.3%), hypertension (3.5%), hemorrhagic events (2.3%), hypersensitivity (1.3%)Monitoring Parameters
- Liver function tests (ALT, AST, bilirubin) at baseline, every 2 weeks for first 3 months, then monthly
- ECG and electrolytes at baseline and periodically during treatment
- Blood pressure regularly
- Complete blood count with differential
- Fasting glucose and electrolytes (calcium, magnesium, potassium)
- Signs and symptoms of bleeding
- Tumor response assessment per RECIST v1.1
Patient Education
- Take exactly as prescribed, approximately every 12 hours with or without food
- Do not crush or open capsules
- Report any signs of liver problems (jaundice, dark urine, nausea, vomiting)
- Monitor blood pressure regularly and report significant increases
- Report signs of bleeding or unusual bruising
- Inform all healthcare providers about Retevmo use, especially before surgeries
- Avoid grapefruit and Seville oranges during treatment
- Use effective contraception during treatment and for at least 1 week after final dose
- Report any signs of allergic reactions (rash, difficulty breathing, swelling)
References
1. FDA prescribing information: Retevmo (selpercatinib). 2020 2. Drilon A, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(9):813-824 3. Wirth LJ, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med. 2020;383(9):825-835 4. Subbiah V, et al. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018;8(7):836-847 5. NCCN Guidelines: Non-Small Cell Lung Cancer. Version 4.2023 6. NCCN Guidelines: Thyroid Carcinoma. Version 2.2023